Even though ketamine has been heralded as a significant advance in the development of novel and rapid treatments for depression, the acute psychotomimetic and reinforcing effects of this drug limit its utility. Previously, we demonstrated that activation of a circuit from the ventral hippocampus to the medial prefrontal cortex is both necessary and sufficient for ketamine?s sustained antidepressant-like effects in rats. In order to test the hypothesis that augmentation of hippocampal activity is capable of producing a sustained antidepressant-like response without also producing abuse-related effects, we evaluated the effects of negative allosteric modulators of alpha-5 GABAA receptors, as these receptors are selectively expressed in the hippocampus. Selective modulation of hippocampal transmission by systemic administration of ?5-GABAA receptor negative allosteric modulator, namely L-655,708, is capable of producing a sustained antidepressant- like effect in the absence of any psychotomimetic or abuse-related effects. In this application, we will utilize conventional pharmacological, electrophysiological, behavioral and chemogenetic approaches to examine the molecular mechanisms by which L-655,708, a negative allosteric modulators the ?5-GABAA receptor, produce sustained antidepressant-like effect. By identifying the mechanisms by which systemic administration of ?5- GABAA receptors negative allosteric modulators recapitulate the therapeutic effects of ketamine without its psychotomimetic and abuse-related effects, it should be possible to provide novel, safe, and effective approaches for treating patients suffering from refractory depression.